Objective: Although the pathogenesis of depression remains unclear, C-reactive protein (CRP) levels are commonly elevated in depressed patients. Thus, CRP single-nucleotide polymorphisms (SNPs) that influence CRP levels may be associated with depression. In the present study, we explored whether CRP SNPs are related to depressive symptoms and antidepressants efficacy in Han Chinese patients. Methods: We analyzed data from 440 patients with first-episode depression. We obtained genome CRP SNPs, scores of the 17-item Hamilton Rating Scale for Depression 17 (HAMD17) and its four-factor at baseline and after 6 weeks. Quantitative trait analysis was performed using UNPHASED software and curative effects were analyzed using SPSS software. Results: Male patients with SNP rs1800947G exhibited lower insomnia scores and rs2794521CC exhibited lower scores of anxiety/ physical symptoms, total HAMD17 score. Female patients with rs2794521TT exhibited higher scores of insomnia and lower antidepressants efficacy. Conclusion: CRP SNPs rs1800947 and rs2794521 may be associated with depressive symptoms in patients with depression in a sex-specific fashion. Furthermore, rs2794521 may be a predictor of the efficacy of antidepressants in female patients.